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EP-4735438-A2 - HETEROBIFUNCTIONAL COMPOUNDS FOR THE DEGRADATION OF KRAS

EP4735438A2EP 4735438 A2EP4735438 A2EP 4735438A2EP-4735438-A2

Abstract

The invention provides compounds that degrade the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein including mutant forms via the ubiquitination of the KRAS protein and subsequent proteasomal degradation. The compounds are useful for the treatment of various cancers.

Inventors

  • ANDERSON, COREY DON
  • CHENG, Xinpeng
  • NASVESCHUK, CHRISTOPHER G.

Assignees

  • Merck Patent GmbH

Dates

Publication Date
20260506
Application Date
20240627

Claims (20)

  1. 1 . A compound of Formula: or a pharmaceutically acceptable salt thereof; wherein: Heterocy clic Moiety A is selected from: and Heterocyclic Moiety B is selected from: and y is L 2, 3, or 4; R 1 and R 6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R 1 and R 6 are combined to form a. one or two carbon bridge to form a fused cycle, each R 2 is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aiyl, heteroaiyl, heterocycle, and -C(O)R 9 , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ; each R 5 is independently selected from hydrogen, alkyl, haloalkyl. alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 7 R 8 , -OR 7 , -SR 7 , -C(O)R 9 , -C(S)R 9 , -S(O)R 9 , -S(O) 2 R 9 , -OC(O)R 9 , -OC(S)R 9 , -OS(O)R 9 , -OS(O) 2 R 9 , -SC(O)R 9 , -OS(O) 2 R 9 , -NR 7 C(O)R 9 , -NR 7 C(S)R 9 , -NR 7 S(O)R 9 , -NR 7 S(O) 2 R 9 , -P(O)(R 9 ) 2 , -SP(O)(R 9 ) 2 , -NR 7 P(O)(R 9 ) 2 , and -OP(O)(R 9 ) 2 ; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ; R 16 is selected from: . and R 12 , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 ; R 17 is selected from: and , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 : R 18 is selected from: and , each of which is attached to the azaglutarimide moiety through a C- N bond and each of which R 18 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RL . R 18B is a. wherein the bicycle is a. 9-membered bicycle which is attached to the azaglutarimide moiety through a C-N bond and is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 3 ; Q is CH 2 , NR 2 , , O, or S; Cycle is a fused aryl or heteroaryl group optionally substituted with 1, 2. 3, or 4 substituents independently selected from R 5 and substituted with one R 12 substituent; Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1 , 2, 3, or 4 substituents independently selected from R 3 and substituted with one R 12 substituent; Cycle-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryd, 5- to 8- membered heterocycle, 5- to 8-membered cycloaikyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-A is optionally substituted with 1 or 2 substituents independently selected from R 3 ; Cycle-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloaikyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-B is optionally substituted with 1 or 2 substituents independently selected from R 5 ; R 12 is the attachment point to Linker; R 7 and R s at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R 14 each of which except hydrogen is optionally substituted with 1. 2, 3, or 4 substituents independently selected from R 10 : each R 9 is independently selected from hy drogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR 7 R*, -OR 7 , find -SR 7 each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ; each R 10 is independently selected from hydrogen, alkyd, haloalkyl. alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR n R 13 , -OR 11 , -SR 11 , -C(O)R 14 , -C(S)R 14 , -S(O)R M , -S(O) 2 R 14 , and -P(O)(R 14 ) 2 , each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2. 3, or 4 substituents independently selected from R |D : R 11 and R 1 -’ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R 14 , -C(S)R 14 , -S(O)R 14 , -S(O) 2 .R 14 , and -P(O)(R 14 ) 2 ; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 15 ; each R 14 is independently- selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and. -N(alkyl')2 each of which except hydrogen is optionally substituted with 1, 2. 3, or 4 substituents independently selected from R 15 - each R 15 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl alkynyl, halogen, aryl, heteroaryl. heterocycle, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)-2; Linker is of Formula: X’ and X 2 are independently at each occurrence selected from bond, heterocycle, NR 2 . C(R 2 ) 2 , O, C(O), and S; R 20 , R 21 , R 22 , R 23 , and R 24 are independently at each occurrence selected from the group consisting of bivalent moieties selected from bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO 2 -, -S(O)-. -C(S)-. -C(O)NR 2 -, -NR 2 C(O)-, -O-. -S-, -NR 2 -. -C(R 40 R 40 )-. -P(O)(OR 26 )O-, -P(O)(OR 26 )-, bicycle, alkene, alkyne, haloalkyl, alkoxy-, aryl, heterocycle, heteroaryl, lactic acid, glycolic acid, find carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 40 , R 26 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, and heterocycle; R 40 is independently- at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(alkyl), -N(alkyl ) 2, -NHSO 2 Calkyl), -N(alkyl)SO 2 alkyl, -NHSO 2 Catyl, heteroaryl or heterocycle), -N(alkyI)SO 2 (aryl, heteroaryl oorr heterocycle), -NHSO 2 alkenyl, -N(aIkyl)SO 2 alkenyl, ~NHSO 2 .alkynyl, -N(alkyl)SO 2 alkynyl. haloalky], aryl, heteroaiyd, heterocycle, and cycloalkyl; KRAS Targeting Ligand A is selected from: KRAS Targeting Ligand B is selected from: KRAS Targeting Ligand' 3 is selected from: KRAS Targeting Ligand D is selected from: or KRAS Targeting Ligand A , KRAS Targeting Ligand B , KRAS Targeting Ligand C , or KRAS Targeting Ligand D , is selected from: KRAS Targeting Ligand E is selected from: KRAS Targeting Ligand F is selected from: R 29 is selected from ary l, heteroaiyl, and bicycle each of which is optionally substituted with 1, 2. 3, or 4 substituents independently selected from R 45 , R 46 , and R 47 ; R 29B is selected from aryl, heteroaiyl, and bicycle each of which is optionally substituted with L 2, 3, or 4 substituents independently selected from R 145 , R 146 , and R 147 : each R 145 , R 146 , and R 147 is independently selected from hydrogen, alkyi. haloalkyl, alkenyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 11 R 13 , -OR 11 , -SR 11 , -C(O)R 14 , -C(S)R 14 , -S(O)R 14 , -S(O).’R 14 , and -P(O)(R 14 )z; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3. or 4 substituents independently selected from R 15 ; R 30 and R 31 are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR, 7 R S , -OR 7 , and -SR 7 ; R 32 is heterocycle optionally substituted with 1, 2. 3, or 4 R 51 groups as allowed by valence; R 4 is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, or bicycle; R 51 is independently selected at each instance from hydrogen, alkyd, haloalkyl, alkenyl, alkynyl. halogen, cyano, nitro. -NR 7 R*, -OR 7 , and -SR 7 ; R 51B is selected from halogen, cyano, haloalkyl, -OR', and -SR 7 ; R 51C is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cyano and CD 3 ; R 51D and R 31E are hydrogen or together with X B and the carbon atoms to which they are attached, form a. 5-. 6-. or 7 -membered ring; z is independently selected at each instance from 0, I , 2, 3, and 4, as allowed by valence; X B is selected from -CH 2 -, -O -. -NH-, -N(R 4 )-, and -S-; X c is -CH 2 -, -O-, or -S-, R 33 is selected from: each of which R 33 IS optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR 7 R 8 , -OR 7 , and -SR 7 ; wherein attachment point is attached to the KRAS Targeting Ligand portion ol the molecule and the remaining attachment point is attached to the Linker; R 33C is each of which R 33C is optionally substituted with 1. 2, 3. or 4 substituents independently selected from alkyl, halogen haloalkyl. alkenyl, alkynyl, aiyd, heteroaryl, heterocycle, bicycle, -NR 7 R 8 , -OR 7 , and -SR'; wherein attachment point is attached to the KRAS Targeting Ligand portion of the molecule and the remaining attachment point is attached to the Linker; R 3 is independently selected from hydrogen, alkyd, haloalkyl. alkenyl, alkynyl, and. heteroaryl, heterocycle, and bicycle; R 33E is each of which R 33E is optionally substituted with 1, 2, 3. or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle. -NR'R S . -OR', and -SR 7 ; wherein attachment point is attached to the KRAS Targeting Ligand portion of the molecule and the remaining attachment point is attached to the Linker; R 3C is independently selected from hydrogen, C2-C8 alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; R 7C is independently selected from hydrogen, C2-C8 alkyl, haloalkyl, alkenyl, alkynyl, and, heteroaryl, heterocycle; and C(O)R 14 each of which except hydrogen is optionally substituted with 1, 2. 3, or 4 substituents independently selected from R 10 ; Xis selected from -O-, -NH-, -N(alkyl)-, and -S-; R 38 and R 39 are independently selected from hydrogen, alkyl, haioalkyi, alkenyl, alkynyl, halogen, aryl, heteroaryl, and heterocycle each of which except hydrogen and halogen is optionally substituted with 1 , 2, 3, or 4 substituents independently selected from R )0 ; R 4i . R 42 , R 4 ' 1 , and R 44 are independently selected from hydrogen, alkyd, haioalkyi, alkenyl, alkynyl, and halogen; each R 43 ,R 46 , find R 4 ' is independently selected from hydrogen, alkyl, haioalkyi. alkenyl, alkynyl, halogen, and. heteroaryl, heterocycle, cyano, nitro. -NR 11 R 13 . -OR 11 , -SR 11 , -C(O)R 14 . -C(S)R 14 , -S(O)R 14 , -S(O) 2 R 14 , and -P(O)(R 14 ) 2 ; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1 , 2, 3, or 4 substituents independently selected from R 15 ; p is 3, 4, 5, 6. 7, or 8; R 133 and R 1 ’ 4 are independently' selected from hydrogen and C1 -C3alky I; or R 133 and R 134 , together with the carbon atom to which they are attached form a C3-C6 cycloalkyl optionally substituted with 1, 2, 3, or 4 halogen atoms as allowed by valence; R 135 and R 136 are independently selected from hydrogen and C1-C6 alkyd; or R 135 and R 136 , together with the nitrogen atom to which they' are attached form a heterocycle, optionally-' substituted with 1, 2, 3. or 4 R 137 groups; R 135 independently selected at each instance from C 1-C6alkyl, C1-C6haloalkyl, -OR 7 , - NR 7 R 8 . and halogen; R 3213 is selected from: q is L 2, or 3: w is 1, 2, or 3; X D is selected from -CH 2 -, -O-, and -S-; R 32C is selected from: R ' ; is independently selected at each instance from hydrogen, C2-C8 alkyl, haloaikyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR 77 R 88 , -OR 7 , and -SR 7 ; R" and R 88 at each instance are independently selected from hydrogen, alkyl, haloaikyl, alkenyl, alkynyl, aryl, heteroaiyl, heterocycle: and C(O)R 114 each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ; each R 114 is independently selected from hydrogen. C2-C8 alkyl, haloaikyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, -O-C 2 -C8 alkyl, -N(H)falkyl), and -N(alkyl) 2 each of which except hydrogen is optionally substituted with 1 , 2, 3, or 4 substituents independently selected from R 15 ; X E is selected from -O-, and -S-; qq is 2, or 3; each of which R 53D is optionally substituted with 1. 2, 3, or 4 substituents independently selected from alkyl, halogen haloaikyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR 7 R 8 , - OR 7 , and -SR 7 : w herein attachment point is attached to the KRAS Targeting Ligand portion of the molecule and the remaining attachment point is attached to the Linker; zz is independently 1, 2, 3, or 4, R 29C is selected from aryl, heteroaiyl, and bicycle each of which is optionally substituted with 1, 2, 3. or 4 substituents independently selected from R 45C , R 46C , and R 47C ; each R 4 4 5 S C C , R 46C , and R 47C is independently selected from hydrogen, Cj-C® alkyl, haloaikyl, alkenyl, halogen, aryl, heteroaiyl, heterocycle, cyano, nitro, -NR i r R L ', -OR 11 , -SR 11 , -C(O)R 14 , -C(S)R 14 , -S(O)R 14 , -S(O)2R 14 , and -P(O)(R’ !4 )2: each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1. 2, 3, or 4 substituents independently selected from R 13 ; R29D is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2. 3, or 4 substituents independently selected from R 45D , R 461) . and R 47B ; each R 451 ’, R 46B , and R 47D is independently selected from hydrogen, alkyl, haloaikyl, alkenyl, alkynyl, chloro, bromo, aryl, heteroaiyl, heterocycle, cyano, nitro, -NR n R 13 , -O-alkyl, -SR 11 , -C(O)R 14 , -C(S)R 14 , -S(O)R 14 , -S(O) 2 R 14 , and -P(O)(R 14 ) 2 ; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R i5 ; R 29E is selected from phenyl and heteroaiyi each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 4 ', R 46 , and R 4 '; and R 31B IS independently selected from alkyl, haloalkyi, alkenyl, alkynyl, halogen, cyano, nitro, -NR 7 R 8 , -OR 7 , and -SR 7 .
  2. 2. ’The compound of claim I, wherein Heterocyclic Moiety A and Heterocyclic Moiety B are
  3. 3. The compound of claim 2, wherein Q is NH. NCHs. O, or S.
  4. 4. The compound of claim 1, wherein Heterocyclic Moiety 8 is
  5. 5. The compound of any one of claims 1-4. wherein R 1 is hydrogen.
  6. 6. The compound of any one of claims 1-5, wherein R 16 and R 17 are selected from
  7. 7. The compound of any one of claims 1-5, wherein R 16 and R 17 are selected from
  8. 8. The compound of claim 1, wherein Heterocyclic Moiety A and Heterocyclic Moiety® are
  9. 9. The compound of claim 8. wherein R 18 is optionally substituted with 1 , 2, 3, or 4 substituents independently selected from R 5 .
  10. 10. The compound of claim 8, wherein R 18 and R 18B are
  11. 11. The compound of claim 1, wherein Heterocyclic Moiety A B are
  12. 12. The compound of any one of claims 1-11, wherein R 6 is hydrogen.
  13. 13. The compound of any one of claims 1 -12, wherein each R ? is independently selected from hydrogen, alkyl, haloalkyl, and halogen.
  14. 14. The compound of any one of claims 1-13, wherein Linker is of formula:
  15. 15. The compound of any one of claims 1-14, wherein X 1 is bond, heterocycle, or -NR 2 -.
  16. 16. The compound of any one of claims 1-15, wherein R 23 is bond, heterocycle, or -NR 2 -.
  17. 17. The compound of any one of claims 1-16, wherein R 20 is alkyl, heterocycle, aryl, -heteroaryl or bicycle, each of which is optionally substituted with 1 or 2 substituents independently selected from R 40 .
  18. 18. The compound of any one of claims 1-17, wherein R 2i is bond, -O-, -NR 2 -, -S-, alkyl, heterocycle, and, heteroaryl, or bicycle, each of which is optionally substituted with 1 or 2 substituents independently selected from R 4u .
  19. 19. The compound of any one of claims 1-18, wherein R 22 is alkyl, heterocycle, aryl, heteroaryl, or bicycle, each of which is optionally substituted with 1 or 2 substituents independently selected from R 40 .
  20. 20. The compound of any one of claims 1-19, wherein the compound is of Formula or a pharmaceutically acceptable stilt thereof, wherein KRAS Targeting Ligand 33 is , or

Description

HETEROBIFUNCTIONAL COMPOUNDS FOR THE DEGRADATION OF KRAS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63/524,459 filed June 30, 2023, which is incorporated by reference herein for all purposes. FIELD OF THE INVENTION The invention provides compounds that degrade a Kirsten rat sarcoma viral oncogene homolog (KRAS) protein, for example a mutant KRAS protein such as G12D-KRAS or gain- of-function KRAS mutations, for the treatment of abnormal cellular proliferation including cancers and tumors as described in more detail below. BACKGROUND OF THE INVENTION The rat sarcoma (RAS) family of viral oncogene homolog GTPases are involved in cellular signal transduction by acting as molecular switches to mediate cell growth, differentiation, and survival. The RAS family includes three distinct members, i.e. Harvey rat sarcoma viral oncogene homolog (HRAS), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Neuroblastoma rat sarcoma viral oncogene homolog (NRAS). Upon GTP binding, the RAS GTPases engage effector proteins to initiate a variety of downstream signaling including the RAF-MEK-ERK and PI3K-AKT pathways that control mitogenic processes (Cox, A.D. & Der, C.J. Ras history: The saga continues. Small GTPases. 1(1):2- 27(2010 Jul.)). Overexpression or mutation of these genes leads to the accumulation of GTP- bound KRAS and the unrestricted activation of RAF-MEK-ERK and PI3K-AKT signaling pathways and has been implicated in many types of human cancer including colorectal cancer, pancreatic cancer, lung cancer, and non-small cell lung cancer (NSCLC). Single amino acid substitutions caused by missense mutations are associated with 98% of RAS-related cancers and occur at mutational hotspots encoding codons including glycine-12 (G12), glycine-13 (G13), and glutamine-61 (Q61) (Waters, A.M. & Der, C.J. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb. Perspect. Med.8(9):a031435(2018 Sep)). Mutant KRAS accounts for approximately 84% of all RAS- mutant cancers (Id.). Gain-of-function KRAS mutations are found in approximately 30% of all human cancers (P. Liu et al., “Targeting the untargetable KRAS in cancer therapy”. Acta Pharm. Sinica B 2019; 9(5): 871–879; V. Merz et al., “Targeting KRAS: The Elephant in the Room of Epithelial Cancers”. Front. Oncol.2021, vol. 11, article 638360), including, e.g., pancreatic cancer (>80%), colon cancer (approximately 40-50%), lung cancer (approximately 30-50%), non-small cell lung cancer, myeloid leukemia breast cancer, cervical cancer, endometrial cancer, liver cancer, bladder cancer, and biliary tract malignancies (S. Jančík et al., “Clinical Relevance of KRAS in Human Cancers” J. Biomed. Biotechnol. 2010; 2010: 150960). Activating or gain-of-function mutations interfere with KRAS’s ability to flip between active and inactive states. Patients with KRAS mutations have historically exhibited poor responses to standard of care therapies. Despite the known role of KRAS as an oncogenic hub, the development of KRAS targeting agents has historically been extremely challenging, even earning the nickname, “the undruggable gene” (Parikh, K. et al. Drugging KRAS: current perspectives and state-of-art review. J Hematol Oncol.15:152(2022)). In 2013, the lab of Kevan Shokat at the University of California San Francisco identified an allosteric pocket, termed the switch-II pocket, on KRAS which could by bound by inhibitors (Ostrem, J. et al. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature, 503(7477): 548-551). Although this allosteric site is adjacent to the nucleotide binding pocket, it is transiently formed and was not observed in previous crystal structures of the protein. A compound binding in the switch-II pocket alters the relative binding affinity of KRAS to GTP and GDP, favoring the inactive GDP-bound form. Three years later, the first low micromolar compounds against KRAS G12C were disclosed by Wellspring Biosciences (Patricelli, M. et al. Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State. Cancer Discovery 6(3):316-29, 2016). In 2018, Wellspring Biosciences published a paper describing improved KRAS binders with a 4- piperazinyl-quinazolinyl-7-phenol pharmacophore (Janes, M. et al. Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor, Cell, 172, 578-589). Only recently have KRAS targeting agents been developed and approved by the United States Food and Drug Administration (FDA), albeit for a specific subset of KRAS mutant patients (Huang, L. et al. KRAS mutation: from undruggable to druggable in cancer. Sig Transduct Target Ther. 6(1):386(2021 Nov 15)). Sotorasib (Lumakras®) and adagrasib (Krazati®), indicated for locally advanced or metastatic non-small cell lung cancer are irreversible inhibitors of KRAS G12C that covalently bind the mutant cysteine of KRAS, lock